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Oral Communication

Diagnostics and OMICs

Discovering the Real Interactions in Complex Systems: RNAs, Proteins, and Sugars

OC 68.4 - Elucidating new prothrombotic factors by studying the associations of laboratory-measured D-dimer with the circulating blood proteome.

Tuesday, June 27, 2023

15:30 – 15:45 ET

Room: 515

Session Available As: On-Demand

Presenting Author(s)

Kimberley Youkhana, MD

Hematology Fellow
Department of Medicine, University of North Carolina, Chapel Hill
Chapel Hill, North Carolina, United States

Co-Author(s)

AM

Aylin Memili

Genetics Research Specialist
Department of Genetics, University of North Carolina Chapel HIll
Chapel Hill, North Carolina, United States
TB

Traci Bartz

Research Scientist
University of Washington, School of Public Health
Seattle, Washington, United States
JB

Jennifer A. Brody

Research Scientist
Department of Medicine, University of Washington, Seattle WA, USA.
Seattle, Washington, United States
AC

April Carson

Director and Principal Investigator, Jackson Heart Study, NHLBI
University of Mississippi
Jackson, Mississippi, United States
JC

Josef Coresh

Director, George W. Comstock Center for Public Health Research and Prevention
Johns Hopkins University School of Medicine
Baltimore, Maryland, United States
Pd

Paul S. de Vries

Assistant Professor, Epidemiology
Human Genetics & Environmental Sciences, UT Health Houston, School of Public Health
Houston, Texas, United States
MD

Margaret Doyle

Associate Professor of Pathology and Laboratory Medicine
Larner College of Medicine, University of Vermont
Burlington, Vermont, United States
AM

Alanna C. Morrison

Professor, Department of Epidemiology
Human Genetics and Environmental Sciences, University of Texas Health Sciences Center at Houston
Houston, Texas, United States
SR

Stephen Rich

Professor
Center for Public Health Genomics, University of Virginia
Charlottesville, Virginia, United States
JR

Jerome Rotter

Director, Institute for Translational Genomics and Population Sciences
The Lundquist Institute, University of California
Los Angeles, California, United States
NS

Nicholas L. Smith

Professor, Epidemiology
Department of Epidemiology, School of Public Health, University of Washington
Seattle, Washington, United States
KW

Kennan Walker

Director, Multimodal Imaging of Neurodegenerative Disease Unit
Laboratory of Behavioral Neuroscience, National Institute on Aging
Baltimore, Maryland, United States
BY

Bing Yu

Associate Professor and JLH Foundation Chair in Transplant Prevention, Epidemiology
Human Genetics & Environmental Sciences, UT Health Houston, School of Public Health
Houston, Texas, United States
Mary Cushman, MD, MSc (she/her/hers)

Professor
Department of Medicine, Larner College of Medicine at the University of Vermont, USA
Colchester, Vermont, United States
Laura Raffield, PhD (she/her/hers)

Assistant Professor, Department of Genetics
University of North Carolina Chapel Hill
Chapel Hill, North Carolina, United States

Background: D-dimer is a well-established quantitative laboratory marker of thrombosis. Yet, its relationship to the wider proteome is poorly understood. Identifying high-throughput aptamer-based blood proteins associated with D-dimer may elucidate unknown relationships contributing to thrombotic states such as stroke and cardiovascular heart disease (CVD).

Aims: 1) To identify SomaScan-measured proteins associated with laboratory-measured D-dimer in blood samples from large population-based cohorts. 2) To identify less well-understood co-regulated proteins and/or pathways contributing to thrombosis and associated with D-dimer.

Methods: Blood D-dimer and proteomic markers were measured from the same visit in 14,783 participants of the Atherosclerotic Risk in Communities, Cardiovascular Health Study, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis population-based cohorts. The SomaScan platform was used to identify up to 5429 proteins. Multivariable linear regression models were adjusted for age, sex, self-reported race, plate, and batch. Using Bonferroni correction for multiple testing (p < 9.21x10-6, 0.05/5429), fixed effects meta-analysis was performed; results are only presented for proteins observed and tested in at least 2 cohorts.

Results: As shown in figure 1,153 proteins had a statistically significant association with D-dimer. The most significantly associated proteins were- complement component C9 (β=0.162, SE=0.009, p=3.57x10-83), S100-A12 (β = 0.163, SE=0.009, p=1.12x10-82), kallistatin (β= -0.162, SE=0.009, p=1.99x10-82), and alpha-2-antiplasmin (β=-0.153, SE=0.008, p=1.65x10-80) all active in inflammation and/or fibrinolysis. Ten of the 1,153 proteins associated with D-dimer were also previously shown to be associated with cardiovascular events in other studies using the SomaScan platform.

Conclusion(s): We identified 1013 proteins associated with D-dimer in 4 cohorts, 10 proteins were associated with cardiovascular events in previous literature: whereas most remaining proteins have not been previously systematically studied in relation to CVD risk in large samples. We plan to perform pathway analyses to begin to elucidate the contributions of less well-understood, co-regulated thrombosis-related proteins and/or pathways to cardiovascular risk.

Learning Objectives:

Upon completion, participants will be able to appreciate the importance of unraveling the relationship of blood d-dimer to the broader proteome.
Upon completion, participants will be able to articulate which blood proteins identified by the high-throughput SomaScan proteomic platform were associated with laboratory-measured d-dimer in blood samples across several large population-based cohorts.
Upon completion, participants will be able to list at least one non-hemostatic pathway associated with laboratory measured d-dimer.